Neurodegenerative diseases and disorders affect millions of people every year. Such diseases include, Alzheimer's Disease, Parkinson's Disease, Multiple Sclerosis, Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's Disease), Huntington's Disease, Frontotemporal Dementia (Pick's Disease), Prion Diseases, as well as neural diseases and disorders resulting from trauma to the central or peripheral nervous system.
Accordingly, there is considerable interest in the development of stem cell-based therapies for neurodegenerative disease (Abrous et al., Physiol. Rev. 85:523-569 (2005); Picard-Riera et al., J. Neurosci. Res. 76:223-231 (2004); Shors et al., Nature, 410:372-376 (2001); Lie, D. C. et al., Annu. Rev. Pharmacol. Toxicol. 44:399-421 (2004); Jin, K. et al., Proc. Natl. Acad. Sci. USA, 101:343-347 (2004)). However, the molecular mechanisms underlying stem cell fate specification are still poorly understood, and current methods are do not selectively induce differentiation of neural stem cells or neural progenitor cells into neuronal cells. While several agents, including retinoic acid (RA) (Eriksson, P. S. et al., Nature Med. 4:1313-1317 (1998); Palmer, T. D. et al., Mol. Cell Neurosci., 8:389-404 1997), leukemia inhibitory factor (LIF) (Nakashima, K. et al., Science 284:479-482 (1999)) and insulin-like growth factor-1 (IGF-1 (Hsieh, J. et al., J Cell Biol. 164:111-122 (2004)), have been found to direct neuronal, astroglial and oligodendrocytic differentiation, each of these agents are either pleiotropic or have poor activity in vivo.
Thus, there is a need in the art for compositions and methods for inducing selective differentiation of stem cells (e.g., neural stem cells and neuronal progenitor cells) into neurons, both in vivo and in vitro. Moreover, there is a particular need for small molecules that can induce selective differentiation of stem cells into neuronal cells in vivo and in vitro. The present invention satisfies these and other needs.